Over the last years, various approaches have been proposed to improve the delivery of drugs at the target site. First, the drug must be administered by a suitable and easy route, such as orally or rectally, and second the active ingredient must be delivered at the target cells under an active form. There is no device currently available allowing such a vectorized transport of active molecules.
Many publications and patents describe methods for encapsulating active ingredients into nano- or micro-particles, but the issue, to date unsolved, is on one hand to provide an easy route of administration different from the injectable route, i.e. oral or buccal, and on the other hand to have a quasi complete delivery of the active product at the target sites. The best example of this impossibility is the search made for decades to develop an orally administrated insulin. For instance, the delivery systems disclosed so far have permitted an insulin absorption of 2-5% only.
The inventors have previously uncovered that stirring two types of lipids with some metallic salts allowed to increase salt bioavailability and consequently to obtain same therapeutic activity with 1000 to 5000 times lower doses; the potential toxicity of said salts could then be reduced [see U.S. Pat. No. 6,129,924, WO 02/36134 and WO 2004/075990, for instance].
The inventors in particular discovered that certain products, vegetable fractions or complex of these fractions with metals otherwise inactive or insufficiently active as hypocholesterolaemic agents had a considerably increased activities when they were administered in an olive oil solution. This resulted in seeking among the many components of olive oil those which could lead by mixture or reaction with the tested products to more active products. It is in this way that the inventors were able to identify novel products indicated under the term “organometallic complexes”, and obtained by reaction between a derivative of vanadium in oxidation state 4 or 5 and two organic compounds isolated from plant extracts and respectively constituted of sitosterols and acylglycerols.
The inventors also discovered that similar complexes could be prepared from other derivatives of metals wherein the metal is in an oxidation state at least equal to 2 and known for its antidiabetic activity.
They also discovered that similar complexes could be obtained from two types of organic derivatives mentioned previously and various cations of metals useful as biocatalysts in living metabolism, these complexes being, in all the cases, particularly effective agents as vectors of said cations.
“Cations with biocatalytic activity” is understood to cations having a direct biocatalytic activity, and cations capable of substituting for biocatalysts and so modifying certain pathological metabolic pathways. The example of vanadium may be mentioned, which by reason of its similar co-ordination chemistry may substitute for phosphate: thus both acid and alkaline phosphatases are inhibited by vanadyl and vanadate compounds; so too is tyrosine phosphatase which induces a stimulation of the phosphorylation of the tyrosine of the peripheral receptor of insulin as well as of the associated protein kinases.
The present invention now provides a method for preparing reverse micelles, comprising one or more metal salts, such reverse micelles can be administered by any routes, in particular via mucosa and able to cross the cellular membranes. This process advantageously renders possible the control and optimisation of the composition comprising micelles for their later uses in the pharmaceutical and dietetic fields.